1. Field of the Invention
The present invention relates to thiocarbamates and, more specifically, to a synthetic method for preparing S-alkyl and S-aryl thiocarbamates.
2. Description of Related Art
The importance of S-alkyl and S-aryl thiocarbamate compounds as herbicides, pesticides and other biological applications has been recognized for many years. The basic S-alkyl and S-aryl thiocarbamate (S-alkylthiourethane) structure is as follows: 
Such compounds have been of interest due to their numerous biological effects including anesthetic, fungicidal, bactericidal, pesticidal and antiviral activity. These compounds are most noted for their use as commercial herbicides and thus have received considerable attention in the literature. See Maeda, T., DE-Pat. 1817662, Kumiai Chemical Industry Co., LTD.; Chem. Abstr. 74, 12864 (1970); and U.S. Pat. No. 3,582,314 to Konnai et al., which are incorporated herein by reference. They have been used for control of annual grasses and broadleaf weeds and in large-scale on crops such as rice, celery and lettuce.
Earliest reports make use of phosgene as a starting material; however, this reagent is extremely toxic and hazardous to handle, especially in large quantities. Many reports illustrate the intramolecular rearrangement of various derivatives to afford S-alkyl thiocarbamates; however, these rearrangements are extremely limited in starting substrates. See Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410-413; Newman, M. S.; Karmes, H. A. J. Org. Chem. 1966, 31, 3980-3984; Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604-3606; Hackler, R. E.; Balko, T. W. J. Org. Chem. 1973, 38, 2106-2109, all of which are incorporated herein by reference. Similarly, transition metal catalysts containing elements such as palladium, nickel, and rhodium have also been employed to promote rearrangement and product formation. See Jones, W. D.; Reynolds, K. A.; Sperry, C. K.; Lachicotte, R. J.; Godleski, S. A.; Valente, R. R. Organometallics 2000, 19, 1661-1669; Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh, K.; Kurosawa, H. J. Org. Chem. 1999, 64, 7305-7308; Bxc3x6hme, A.; Gais, H.-J. Tetrahedron: Asymmetry 1999, 10, 2511-2514; and Jacob, J.; Reynolds, K. A.; Jones, W. D.; Godleski, S. A.; Valente, R. R. Organometallics 2001, 20, 1028-1031, all of which are incorporated herein by reference. There are a variety of other known methods; however, most require the preparation of complex starting materials. See Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.; Santhakumar, V. Tetrahedron Lett. 1999, 40, 2669-2672, incorporated herein by reference. Carbon monoxide and elemental sulfur are frequently employed in such preparation; however, these methods involve multi-step approaches, which incorporate metal catalysts, or proceed in low yields. The most widely used method for preparation of these compounds makes use of gaseous carbonyl sulfide (COS), which condenses with a secondary amine, followed by subsequent treatment with base and an alkyl halide. This three-step process is limited to secondary amines. See Reddy, T. I.; Bhawal, B. M.; Rajappa, S. Tetrahedron Lett. 1992, 33, 2857-2860, incorporated herein by reference.
Condensation of a thiol with an isocyanate affords the corresponding thiocarbamate; however, this route was only demonstrated when alkoxy and aroxysulfonyl isocyanates were employed. See Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A. J. Fluorine Chem. 1999, 99, 17-24, incorporated herein by reference. Moreover, the hydration of a variety of organic thiocyanates have been reported to afford the desired compound in the presence of hydrogen chloride; however, this method is limited to only N,N-unsubstituted thiocarbamates. See Zil""berman, E. N.; Lazaris, A. Y. J. Gen. Chem. USSR 1963, 33, 1012-1014, incorporated herein by reference. S-alkyl thiocarbamates have also been prepared from salts of dithiocarbamic acid, which are prepared by the addition of secondary amines to carbon disulfide (CS2). See Advanced Organic Chemistry 5th Ed.; Smith, M. B.; March, J., Eds.; Wiley Interscience: New York, 2001; Chapter 16, incorporated herein by reference. Despite being a novel approach, this method is limited to N,N-disubstituted thiocarbamates. Although there are numerous variations, there lacks a simple comprehensive synthetic approach for the facile preparation of both N-substituted, N,N-disubstituted and N,N-unsubstituted S-alkylthiocarbamates.
It is the object of this invention to teach a new synthesis method for the preparation of S-alkylthiocarbamate and S-arylthiocarbamate compounds. This is a one-pot two-step general synthesis of thiocarbamate compounds having two routes to the same product compound depending on the order of reagent addition. In the preferred route, a precursor thiol reagent is first reacted with trichloroacetyl chloride to produce an isolatable S-alkyl or S-aryl trichloroacetyl thioester intermediate, which is then reacted with an amine to yield the corresponding thiocarbamate product. In the alternate route, the amine is first reacted with trichloroacetyl chloride to produce an isolatable trichloroacetamide intermediate, which is then reacted with the precursor thiol to yield the corresponding thiocarbamate product. This new method has the following features and advantages: (1) structural generality (i.e. aliphatic or aromatic thiol used in combination with ammonia, a primary or a secondary amine whose substituents may also be aromatic or aliphatic); (2) facile purification; (3) high isolated yields; (4) one-pot two-step simplified procedures; and (5) avoidance of toxic and environmentally objectionable reagents (e.g. phosgene, carbon monoxide, carbonyl sulfide, carbon disulphide).
A method of preparing S-alkyl and S-aryl thiocarbamates according to a preferred embodiment of the present invention takes advantage of very facile chemistry involving adduct formation between trichloroacetyl chloride (Cl3COCl) and a thiol (1) or an amine (4) followed by a very unique and unexpected chemistry involving nucleophilic displacement of the trichloromethyl moiety as chloroform to yield a variety of thiocarbamate products (3) with various substitutions (R1, R2 and R3) on the sulfur and amine sites as illustrated in Scheme 1. 
It is the unique and unexpected chemistry of the trichloroacetyl thioester adduct (2) and the trichloroacetamide adduct (5) that form the basis of this invention. These adducts undergo nucleophilic substitution reactions resulting, not in regeneration of the initial thiol or amine precursors as might be expected from the general behavior of esters and amides, but in displacement of the trichloromethyl group as chloroform and formation of the thiocarbamate product (3). As depicted in Scheme 1, these adducts serve as intermediate compounds in two complementary routes to the same product. In the upper route adduct 2 undergoes a nucleophilic displacement reaction with an amine reagent, while in the lower route adduct 5 undergoes a nucleophilic displacement reaction with a thiol. The identity of substituents R1, R2 and R3 is determined by the selection of the thiol (1) and amine (4) reagents. This new chemistry provides for a preferred (1xe2x86x922xe2x86x923) route and an alternate route (4xe2x86x925xe2x86x923); the basis for the prefer route being the higher yield.
In the preferred route, the thiol-Cl3COCl adduct (2) is prepared by slow addition of an alkyl or aryl thiol to an excess of the Cl3COCl at 20xc2x0 C. and stirred under dry atmosphere until adduct formation is complete. The molar excess of Cl3COCl may range from a factor of 1.05 to 10 with 2 being preferred. The adduct formation reaction is mildly exothermic and some external temperature control is advisable, although the temperature need not be rigorously maintained at 20xc2x0 C. The formation of compound (2) proceeds rapidly without solvent, and the rate of consumption of the thiol is dependent on the thiol chemical structure in the general order of alkyl greater than benzyl greater than  greater than phenyl. Reaction with the alkyl thiol is complete within about 15 minutes, whereas the benzyl thiol requires about 30 minutes and the phenyl derivative requires approximately 45 minutes to achieve complete conversion. The progress of the reaction is easily monitored by evolution of HCI gas or NMR analysis. Upon completion, the excess Cl3COCl and hydrochloric acid byproduct are readily evaporated or distilled at reduced pressure to yield the essentially pure thioester adduct (2). Although temperature and pressure conditions for evaporation or distillation are not crucial, the preferred temperature and pressure is 120xc2x0 C. and 5 mmHg respectively. Examples of the S-thioester intermediate product are depicted in Table 1.
The second step involves the displacement of the trichloromethyl group of the thioester adduct (2) as chloroform upon treatment with an amine (4) to afford the thiocarbamate product (3). This product may be synthesized with a variety of substituents from a single intermediate (2) by altering the amine employed. Amine reagents include ammonia, primary and secondary amines with aliphatic or aromatic substituents. The transformation of adduct (2) into product (3) is conducted in aqueous or organic media or without solvent depending on the solid or liquid nature and solubilities of the reagents and products. Typically, an excess of amine is added to the thioester adduct (2) in a liquid medium and reacted at a mildly elevated temperature (xcx9c60xc2x0 C.) for several hours. The product (3) is isolated by concentration, distillation, recrystallization and/or chromatography. The molar excess of amine (4) may range from a factor of 1.1 to 10 with a factor of 2 being preferred. When used, solubilizing media may include water and organic solvents. When ammonia is the amine reactant, water is a particularly effective solvent. A solventless system works well when using liquid primary amines, and methanol works well when employing secondary amines. A variety of thiocarbamate products (3) with various substitutions on the sulfur R1 and the amine R2 and R3 sites are prepared in this manner. Examples with aliphatic and aromatic substituents synthesized by this procedure are depicted in Table 2.
The alternate synthesis route in the lower part of Scheme 1 is simply a reversal in order of using the thiol and amine reagents. The trichloroacetamide adduct (5) is formed by the addition of an amine reagent (4) to an excess of Cl3COCl in an organic solvent at a reduced temperature. The molar excess of the Cl3COCl may range from a factor of 1.05 to 10 with a factor of 2 being preferred. Although the temperature is not critical, the optimum temperature is 0xc2x0 C. to prevent ammonium salt formation with excess amine. Likewise, the amine selection is flexible to include those eligible for the preferred route. Also, the use of a solvent system facilitates control of the reaction rate and product formation. Purification of the amine-Cl3COCl adduct (5) may be performed by distillation. Treatment of the adduct (5) in a solution of tetahydrofuran or other suitable solvent at 20xc2x0 C. with an excess of thiol (1) affords the corresponding compound (3) after heating at 100xc2x0 C. for four hours. The excess may range from 1.05 to 10 equivalents with 1.5 being preferred. The temperature is not critical and both the addition and reaction can be performed at a wide range of temperatures with those reported being optimum for maximum yield. The product is isolated by extraction with an organic solvent and sequentially washed with water to remove any unreacted starting materials and byproducts. Additional purification was performed employing flash column chromatography to afford the desired product with yields reported in Table 3.
Methanol was distilled from calcium hydride under nitrogen. Moisture sensitive reactions were conducted in oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Analytical thin-layer chromatography was performed on precoated silica gel sheets, and flash column chromatography was accomplished using silica gel, 60xc3x85 (200-400 mesh). 1H and 13C NMR spectra were taken in CDCl3 at 300 and 75 MHz respectively, with a TMS internal standard. Chemical shifts are reported in units downfield from TMS. Coupling constants, J, are reportrd in units of Hertz (Hz).